Cellular populations in the nervous system vary in their demographics: They differ in their size, positioning, intercellular spacing, dendritic overlap, and connectivity. This research program has been identifying the genetic sources of this variation and analyzing the interdependencies between these population dynamics, using the retina as a model system and a panel of twenty-six genetically distinct recombinant inbred mouse strains. Neuron number varies considerably across these strains of mice, for every different type of retinal neuron analyzed to date, and this variation maps to discrete and largely independent genomic loci for each cell type, showing minimal evidence for genetic co-regulation. The present proposal will continue to explore the genetic sources of such variation in cell number, focusing upon different populations of retinal interneurons, and how such variation in their cell number affects those other demographic traits, via four new specific aims.
Specific Aim 1 will extend our use of quantitative trait locus (QTL) mapping strategies to identify epistatic interactions controlling the variation in retinal cell number. It will identify candidate genes at interacting genomic loci, and demonstrate their genetic interaction directly.
Specific Aim 2 will examine the role of the Rbfox gene family in retinal development, and identify changes in alternative splice transcripts in the absence of RBFOX function.
Specific Aim 3 will define the role of the transcription factor, Nfia, in the selective control of AII amacrine cell number. It will assess the alternative splicing of Nfia as a function of development, and examine the functional properties of developmentally regulated isoforms.
Specific Aim 4 will define the degree of dependency of VGluT3 amacrine cell differentiation upon the density and intercellular spacing of these cells, seeking to understand the role played by homotypic interactions in regulating retinal coverage. The present research proposal will thereby identify the genetic determinants and intercellular interactions that underlie the demographic features of cellular populations in the retina. These studies will clarify our understanding of retinal development and identify novel genes and their variants that may contribute to developmental disorders of the nervous system, together informing the emerging field of regenerative medicine.

Public Health Relevance

This research program will identify the determinants of the demographic properties of various cell types within the retina, including the absolute number of cells within a population, the patterning established by their intercellular spacing, and the manner by which they distribute their processes to generate their coverage upon the retina. It will clarify the co-dependencies of these different population dynamics, and identify the cellular, molecular and genetic mechanisms that underlie them. These studies will reveal the developmental processes that produce the functional architecture of the retina, contributing to our understanding of developmental disorders of the nervous system, and providing a knowledge base for the emerging field of neural regenerative medicine.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Molecular Neurogenetics Study Section (MNG)
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Greenwell, Thomas
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University of California Santa Barbara
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Santa Barbara
United States
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Reese, Benjamin E (2018) Axon Terminal Arbors of Retinal Horizontal Cells Lose Control. Front Neural Circuits 12:82
Sankaran, Mathangi; Keeley, Patrick W; He, Li et al. (2018) Dopaminergic amacrine cell number, plexus density, and dopamine content in the mouse retina: Strain differences and effects of Bax gene disruption. Exp Eye Res 177:208-212
Keeley, Patrick W; Reese, Benjamin E (2018) The somal patterning of the AII amacrine cell mosaic in the mouse retina is indistinguishable from random simulations matched for density and constrained by soma size. Vis Neurosci 35:E003
Stincic, Todd L; Keeley, Patrick W; Reese, Benjamin E et al. (2018) Bistratified starburst amacrine cells in Sox2 conditional knockout mouse retina display ON and OFF responses. J Neurophysiol 120:2121-2129
Kautzman, Amanda G; Keeley, Patrick W; Borhanian, Sarra et al. (2018) Genetic Control of Rod Bipolar Cell Number in the Mouse Retina. Front Neurosci 12:285
Keeley, Patrick W; Reese, Benjamin E (2018) DNER and NFIA are expressed by developing and mature AII amacrine cells in the mouse retina. J Comp Neurol 526:467-479
Kautzman, Amanda G; Keeley, Patrick W; Nahmou, Michael M et al. (2018) Sox2 regulates astrocytic and vascular development in the retina. Glia 66:623-636
Kautzman, Amanda G; Keeley, Patrick W; Ackley, Caroline R et al. (2018) Xkr8 Modulates Bipolar Cell Number in the Mouse Retina. Front Neurosci 12:876
Keeley, Patrick W; Whitney, Irene E; Reese, Benjamin E (2017) Genomic Control of Retinal Cell Number: Challenges, Protocol, and Results. Methods Mol Biol 1488:365-390
Puller, Christian; Arbogast, Patrick; Keeley, Patrick W et al. (2017) Dendritic stratification differs among retinal OFF bipolar cell types in the absence of rod photoreceptors. PLoS One 12:e0173455

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